During the past nine years, the University of Colorado SPORE in Lung Cancer has developed a team of basic scientists, pathologists, pulmonologists, medical oncologists, biostatisticians and population scientists who share goals of discovering new knowledge regarding the biology of lung preneoplasia and cancer and translating that knowledge to improved prevention, diagnosis and treatment. We have also developed cohorts for cross-sectional case control, longitudinal and nested case control studies of lung cancer risk. We are carrying out several chemoprevention studies that contribute to the cohorts and promote discovery of the response of the airway epithelium to intervention. One of nine smokers develops lung cancer. We seek to improve our ability to assess lung cancer risk beyond smoking history so that early detection and chemoprevention efforts may be more appropriately focused. The overall objective of this project is to identify markers of neoplastic change in the respiratory epithelium that hold clinical promise for assessment of risk and response to chemoprevention. This objective is based on the hypothesis that a field effect of widespread genetic and epigenetic alterations in the respiratory epithelium precedes and thereby reflects risk for lung cancer development. All 5 Colorado SPORE projects and a Johns Hopkins SPORE project are collaborating in the discovery of biomarkers that will be developed in this project. The majority of biomarker assays will be carried out by Project 5. There are two goals for this project: 1) To develop a set of risk assessment biomarkers in sputum and tissue samples by evaluating the association between tobacco smoke exposure, candidate biomarkers and development of lung cancer. 2) To assess the response of candidate intermediate endpoint biomarkers in chemoprevention trials to identify those markers that are most likely to be useful as surrogate endpoints of either pharmacologic or biologic response. The following Specific Aims will be pursued: 1) Determine genes differentially expressed in bronchial epithelium of individuals with varying degrees of current or past tobacco smoke exposure and with varying degrees of histologic dysplasia. We will develop biomarker assays for genes with expression patterns that suggest they will be useful biomarkers of lung cancer risk. 2) Assess the reliability of assays for biomarkers from this project and others. 3) Conduct cross sectional studies among lung cancer cases and individuals at varying risk for development of lung cancer to assess the association between biomarkers, tobacco smoke exposure, and lung cancer risk. 4) Validate selected biomarkers as predictors of lung cancer risk in longitudinal cohort and nested case control studies from our high risk cohort and from other collaborating cohorts. 5) Assess the responses of biomarkers to agents that have known effects on specific pathways in the context of four chemoprevention trials.